The overall goal of our original proposal was to test the hypothesis that concomitant HIV-1 infection impairs clearance of Treponema pallidum from the CSF. The progress that we have made in the first funding period supports our hypothesis. Specifically, individuals with more pronounced HIV-1-mediated immunosuppression are more likely to have neurosyphillis, and normalization of CSF WBC count and serum RPR after treatment for neurosyphilis is slower and less complete in HIV-1-infected individuals. Few studies have addressed the influence of concomitant HIV-1 on CNS infection by T. pallidum. In our study to date, we have enrolled and obtained CSF from 348 subjects with all stages of syphilis. Approximately three-quarters of our subjects are also HIV-1-infected. To date, 53 subjects have had at least one follow-uplumbar puncture. Our ongoing study represents the largest investigation of neurosyphilis in many decades, and is the only study with sufficient power to address the effect of concurrent HIV-1-infection on development of neurosyphilis and the response to neurosyphilis therapy in HIV-1-infected and -uninfected individuals. In this competing renewal application, we focus on three clinically important questions. These questions and the principal hypotheses to be tested for each are: 1) Which HIV-1-infected and -uninfected patients with syphilis should undergo lumbar puncture to evaluate the possibility of neurosyphilis? We hypothesize that individuals with higher concentrations of T. pallidum in blood, those with particular strain types in blood and those with greater diversity of blood T. pallidum strains will be more likely to have neurosyphilis. We will test these hypotheses in Specific Aim 1; 2) How can CSF pleocytosis due to infection with T. pallidum be distinguished from CSF pleocytosis due to HIV-1 infection? We hypothesize that the CSF cellular phenotype and that production of T. pallidum-specific antibody by CSF lymphocytes will distinguish T. pallidum-induced from HIV-1-induced CSF pleocytosis. We will test these hypotheses in Specific Aim 2; and 3) What factors determine response to therapy in HIV-1-infected and -uninfected patients with neurosyphilis? We hypothesize that rapidity and completeness of response to treatment will be related to CSF T. pallidum concentration and to CSF T. pallidum strain type. We will test these hypotheses in Specific Aim 3. The studies proposed in this application are directly relevant to the care of patients with HIV-1 and with syphilis and will ultimately improve our ability to diagnose and treat neurosyphilis.